Molecular Genetics of Tau-Associated Neurodegeneration

Tau 相关神经变性的分子遗传学

• 批准号: 6820962
• 负责人: GEORGE R JACKSON
• 金额: $ 35.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820962
• 关键词: Alzheimer' s disease; Drosophilidae; aminopeptidase; arthropod genetics; cytotoxicity; disease /disorder model; gene mutation; genetic screening; genetically modified animals; molecular pathology; neural degeneration; neurofibrillary tangles; phosphorylation; protein isoforms; tau proteins

DESCRIPTION (provided by applicant): Mutations in the microtubule-associated protein tau occur in some cases of inherited frontotemporal dementia (FTD), demonstrating that tau abnormalities can cause neurodegeneration. Many FTD mutations occur in regulatory elements that alter splicing and thereby expression of tau isoforms, rather than tau coding sequence. One of the hallmark neuropathologic features of Alzheimer's disease (AD) is the neurofibrillary tangle (NFT), which contains hyperphosphorylated tau. Characterization of the events that modify tau-associated neurodegenerative processes is critical for understanding the pathophysiology of AD, as well as FTD and related diseases, such as progressive supranuclear palsy and corticobasal degeneration, and for the development of therapeutics. In order to test the hypothesis that neurodegeneration can be caused by aberrant expression of wild-type tau, the longest isoform of human tau was overexpressed in the fruit fly, producing degeneration of the eye and underlying brain, but failing to produce neurofibrillary tangles. However, tau phosphorylation by co-expression of shaggy, the Drosophila homologue of glycogen synthase kinase (GSK)-3beta, an important tau kinase in vitro, produced a more severely degenerated eye, as well as lesions resembling NFT (Jackson, G.R., et al. (2002): Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34: 509-519). Here, we will examine whether Shaggy is incorporated into NFT-like lesions in double tau + Shaggy transgenics. We will examine the role of puromycin-sensitive aminopeptidase, which was identified in a pilot screen, as a tau modifier. Finally, we will perform loss of function and gain of function genetic screens in order to identify novel modifiers of the abnormal Drosophila phenotype associated with expression of hyperphosphorylated tau. Modifier genes will be characterized and evaluated as targets for the development of new therapies aimed at alleviating neurofibrillary pathology and neuronal cell death in AD and other neurodegenerative disorders.

描述（由申请人提供）：微管相关蛋白 tau 突变发生在某些遗传性额颞叶痴呆 (FTD) 病例中，表明 tau 蛋白异常可导致神经变性。许多 FTD 突变发生在调节元件中，这些元件改变剪接，从而改变 tau 异构体的表达，而不是改变 tau 编码序列。阿尔茨海默病 (AD) 的标志性神经病理学特征之一是神经原纤维缠结 (NFT)，其中含有过度磷酸化的 tau 蛋白。表征 tau 相关神经退行性过程的事件对于理解 AD 的病理生理学以及 FTD 和相关疾病（例如进行性核上性麻痹和皮质基底节变性）以及治疗方法的开发至关重要。为了检验神经变性可能是由野生型 tau 的异常表达引起的假设，人类 tau 的最长异构体在果蝇中过度表达，导致眼睛和底层大脑变性，但无法产生神经原纤维缠结。然而，通过与糖原合酶激酶 (GSK)-3β（一种重要的体外 tau 激酶）果蝇同源物 shaggy 共表达而导致的 tau 磷酸化，产生了更严重的退化眼睛以及类似 NFT 的病变（Jackson，G.R. 等） al. (2002)：人类野生型 tau 蛋白与无翼通路成分相互作用，并在果蝇神经元中产生神经原纤维病理。 34：509-519）。在这里，我们将检查 Shaggy 是否被纳入双 tau + Shaggy 转基因中的 NFT 样病变中。我们将研究在试点筛选中鉴定出的嘌呤霉素敏感氨肽酶作为 tau 修饰剂的作用。最后，我们将进行功能丧失和功能获得遗传筛选，以确定与过度磷酸化 tau 表达相关的果蝇异常表型的新修饰因子。修饰基因将被表征和评估，作为开发新疗法的目标，旨在减轻 AD 和其他神经退行性疾病中的神经原纤维病理和神经元细胞死亡。